Basic Overview of Mast Cell Disorders

Primary	Secondary	Idiopathic
Mastocytosis Cutaneous Systemic Monoclonal mast cell activation syndrome (MMAS) Mast cell sarcoma Mastocytoma	IgE-mediated hypersensitivity reactions (e.g., food, insect, drug-induced anaphylaxis) Drug-induced "anaphylactoid" reactions (e.g., vancomycin, opioids, taxanes) Mast cell hyperplasia (associated with chronic infections, neoplasia, and autoimmune conditions, possibly due to an excess of stem cell factor; these reactive states are infrequently the cause of mast cell activation disorders) Chronic autoimmune urticaria Physical urticarias	Mast cell activation syndrome (MCAS) MCAS should be assigned to patients whose symptoms do not meet the clinical definition of anaphylaxis; if the criteria for anaphylaxis is met then the diagnosis idiopathic anaphylaxis is more appropriate Idiopathic anaphylaxis Chronic idiopathic urticaria or angioedema

Direct Mast Cell Degranulation Triggers

• Insect stings, envenomations
  • Hymenoptera
  • Jellyfish
  • Snakes
• Drugs
  • Narcotic analgesics (eg, codeine, morphine)
  • Radiocontrast materials
  • Aspirin and NSAIDs
  • Muscle relaxants
  • Some antibiotics (eg, vancomycin, cephalosporins)
• Changes in temperature (heat, cold)
• Mechanical irritation (massage, friction, pressure)
• Invasive procedures (e.g. surgery, biopsies, endoscopy)
• Other
  • Alcohol
  • Emotional stress
  • Exercise
  • Very spicy foods
  • Infections (viral, bacterial, parasitic)
  • Fever

Note:

• In patients with MCAS, alcohol and heat are the most common triggers of symptoms
• Hymenoptera stings are frequently triggers in MMAS and MCAS and can be the sole manifestation of the disease

Diagnosis

Mastocytosis WHO Criteria

• Note:
  • >90% of adult patients with SM have a D816V point mutation in c-KIT gene
  • All patients with SM have bone marrow involvement
  • Gut involvement in SM may be patchy and multiple biopsies may be needed to demonstrate mastocytosis
    • In one study mast cells in duodenal biopsies ranged from 4-51/hpf in normals vs. 74-339/hpf in SM
    • CD25 expression by mast cells seems to be a more reliable marker than the absolute mast cell numbers
    • Reactive mast cell hyperplasia can be seen as a response to other intestinal disorders (IBD, infection, etc.)
  • In children, cutaneous mastocytosis is rarely associated with systemic disease and therefore a bone marrow biopsy is unwarranted
    • Despite the absence of systemic disease, the local release of mediators from skin mast cells is sufficient to cause systemic symptoms of mediator release, and such an occurrence should not be misinterpreted as a sign of systemic disease
    • Vast majority of children will undergo spontaneous resolution of CM before puberty, and watchful waiting is recommended unless there is hepatosplenomegaly, lymphadenopathy, CBC abnormalities, or persistently elevated/increasing tryptase >20 ng/mL
  • 20% of patients with indolent SM have tryptase <20 ng/mL

Clinical features UNLIKELY to be SM or mast cell-mediated	MORE LIKELY to be SM or mast cell-mediated	Pitfall Diagnoses
Hypertensive spells Symptoms that improve with medications not targeting mast cell mediators or their effects (e.g. medications for anxiety or depression Seizure activity; incontinence (Delayed) problems with memory Dementia Arthritic complaints involving small joints or involving muscles Chronic urticaria, AD, or eczema Delayed reactions to medications Rhinitis or rhinosinusitis Food allergy Non-anaphylactic reactions to beestings, fire ants, horseflies	Urticaria pigmentosa, positive Darier’s sign Mast cell mediator-related symptoms (i.e. flushing, warmth, pruritus, abdominal cramps, diarrhea, bronchospasm, tachycardia, syncope) Symptoms respond to epinephrine, antihistamines, sodium cromolyn Anaphylaxis to hymenoptera stings Recurring episodes of tachycardia not responding to cardiac medications (β-blockers) or a pacemaker Idiopathic anaphylaxis Males with osteoporosis Eosinophilia Anaphylactic response to NSAIDs (90-95% of mastocytosis patients do tolerate them)	Carcinoid - briefer flush, worsened by epinephrine (vs beneficial response in SM) Common flushing, climacteric flushing (hot flashes) Disorders of hyper/hypohidrosis Spells Endocrine: pheochromocytoma, thyrotoxicosis, medullary thyroid carcinoma, insulinoma, hypoglycemia CV: labile HTN, deconditioning, pulmonary edema, syncope, orthostatic hypotension, paroxysmal arrhythmias Psych: somatization disorder, hyperventilation, panic attacks Pharmacologic: withdrawal of alpha/beta blockers, MAO treatment plus tyramine ingestion, sympathomimetic ingestion, illegal drug ingestion, chlorpropamide-alcohol flush, vancomycin red-man syndrome Neuro: postural orthostatic tachycardia syndrome, autonomic neuropathy, migraine headache, seizure disorders, stroke, cerebrovascular insufficiency Simple faint, vasovagal episodes

MCAS Diagnostic Criteria

SM - systemic mastocytosis, MMAS - monoclonal mast cell activation syndrome, MCAS - mast cell activation syndrome, IA - idiopathic anaphylaxis, UP - urticaria pigmentosa

Note:

• Anaphylaxis with hypotension seems to be more common in clonal mast cell disorders (i.e. SM or MMAS) vs. urticaria/AE which seems to be more common in MCAS
  • Anaphylaxis to hymenoptera should raise suspicion for clonal mast cell disorders
  • Other strong risk factors for clonal mast cell disorders are male sex, syncopal episode without accompanying urticaria/AE, tryptase >25 ng/mL
• c-KIT (CD117) D816V mutation test currently available

Mast Cell Disorder Diagnostic Algorithms (Castells, Akdis)

To rule out alternative disorders (carcinoid, pheochromocytoma, gastrinoma, VIPoma, medullary thyroid carcinoma), recommended tests include:

• 24 hour urine 5-hydroxyindoleacetic acid (5-HIAA)
• 24 hour urine fractionated catecholamines and metanephrines
• Serum VIP
• Serum calcitonin

Lab evaluation to be obtained while symptomatic:

• Look for elevated serum tryptase (11.4 ng/mL) OR relative increase in serum total tryptase (drawn during or within 4 h of symptoms):
  • Serum tryptase while symptomatic > 1.2 x baseline tryptase + 2 ng/mL = sign of significant mast cell activation
• 24 hour urine collection for N-methylhistamine, prostaglandin-D2, or its metabolite 11β-prostaglandin F2α
  • Meaningful elevation cutoffs for these substances have not been established and these results should be approached with caution

SM Diagnostic Algorithm (Pardanani 2013)

ECNM Algorithm (2014) and REMA score

Note:

• In childhood patients with MIS, a bone marrow investigation is not recommended unless serum tryptase levels are very high (>100 ng/ml) or the blood count and/or other clinical findings and symptoms suggest the presence of a hematologic neoplasm

Note:

• In those with normal or slightly increased tryptase level and a REMA score <2, it is helpful to examine peripheral blood cells for the presence of KIT D816V
• In patients in whom typical signs and symptoms (e.g. osteoporosis, histamine-induced symptoms, increased histamine metabolite excretion, unexplained anaphylaxis) or KIT D816V are detected, a BM examination should be performed.

REMA Score

Practical Management of Incidental High Tryptase Level

• In a patient with anaphylaxis (e.g. to venom) and high baseline tryptase level (Schwartz)
  • Whether a diagnosis of a mast cell clonality disorder (e.g. via bone marrow biopsy) is needed in all cases is open for discussion
  • If there is no evidence for organ impairment (including the hematopoietic and GI/hepatobiliary systems), then an examination of bone health (osteoporosis, osteosclerosis) and regular follow-up visits (including CBC/diff, CMP, tryptase) every 6-12 months may be satisfactory
  • Many patients with indolent SM have stable disease for decades and only a few may have a more aggressive component or transform into a more aggressive form of mastocytosis
  • Curative interventions or safe long-term cytoreductive therapies for indolent SM are not available

• Bone marrow biopsy indications (Castells)
  • Serum total tryptase >20 ng/ml, or >11.4 ng/ml in patients with a history of hypotensive episodes and/or syncope
  • Additional factors
    • Urticaria pigmentosa (UP) on skin examination of adult patients
    • CBC/diff abnormalities (which may suggest SM with an associated hematologic non-mast cell lineage disease (SM-AHNMD), myeloid or mastocytic leukemia, myeloproliferative or myelodysplastic disease)
      • These patients usually have cytopenias or thrombocytosis and/or leukocytosis on CBC, are male, have fewer skin symptoms, and are older than patients with pure SM
    • Unexplained anaphylaxis (especially in the setting of sting reaction with negative sIgE testing to hymenoptera)
    • Unexplained osteoporosis, hepatomegaly, or splenomegaly in patients with a mast cell activation disorder raises suspicion for an aggressive variant of SM

• Bone marrow biopsy indications (Akin)
  • Consider a bone marrow biopsy of patients with baseline tryptase >20 ng/mL or those who have syncopal or presyncopal events as part of their symptomatology (regardless of tryptase levels), whereas the presence of chronic urticaria or angioedema would be a deterrent to recommend this procedure
    • Analysis of peripheral blood for D816V c-kit mutation can be considered and its presence would help in deciding whether the patient needs a bone marrow biopsy
    • A bone marrow biopsy is recommended in all adult patients with urticaria pigmentosa because almost all patients in this group have evidence of bone marrow involvement
      • Most pediatric patients with onset of skin lesions in the first 2 years of life have disease limited to the skin and watchful waiting is appropriate in these patients unless they have another indication to do a bone marrow biopsy (e.g., unexplained abnormalities in CBC/diff, liver, spleen, or lymph node enlargement, or progressively increasing tryptase levels higher than 20 ng/mL)

• Bone marrow biopsy indications (Van Doormaal)
  • In suspected patients without UP, the indolent SM risk is very low (if present at all) if tryptase is <10 μg/l, therefore bone marrow examination is not recommended
  • If tryptase is ≥10 μg/l, the risk depends on urinary histamine metabolites methylimidazole acetic acid and methylhistamine, with the risk being low if these are normal, but high if these are elevated
  • Male gender and insect venom anaphylaxis are additional risk factors

MCAS Treatment (Castells)

• Castells: start Gastrocrom (sodium cromolyn) at 100 mg QD titrating weekly up to 200 mg QID; may treat GI as well as skin and CNS symptoms despite poor systemic absorption
• Akin:
  • Systemic steroids may be required, and if the patient responds, then a slow taper over a few months should be attempted; some require a small maintenance dose (<7.5 mg QD or every other day equivalent dose of prednisone)
  • Patients with diarrhea due to MCAS or SM have been exceptionally responsive to steroids (even in low doses); lack of response to steroids would argue strongly against a mast cell disorder
• Quercetin - flavonoid plant pigment widely distributed in nature, may inhibit mast cell degranulation, available OTC as a supplement
• Tyrosine kinase inhibitors (TKI) for SM
  • Most TKIs (incluidng imatinib) are ineffective against the D816V KIT mutation (affects >90% of patients with SM)
  • A newer TKI (midostaurin) has shown promising efficacy in patients with the D816V KIT mutation

Mast Cell Distribution

References